Risperidone pamoate

ABSTRACT

A compound which is a pamoate acid addition salt of risperidone, compositions comprising the same and processes for preparing said compound and compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based upon PCT application Ser. No. PCT/EP 94/01296,filed Apr. 22, 1994, which claims priority from European PatentApplication Ser. No. 93.201.216.4, filed on Apr. 28, 1993.

EP-0,196,132 discloses the compound3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,that is known genetically as risperidone and is a potent antipsychotic.Unfortunately, the current formulations of risperidone only yieldeffective plasma levels during a limited time interval. Long-actinginjectable risperidone dosage forms would be valuable in maintenancetherapy and would enhance patient compliance.

Currently available long-acting neuroleptics include solutions in oils,e.g. sesame oil, of poorly water-soluble ester derivatives of theneuroleptic compounds. Trials to prolong the activity of some particularphenothiazine neuroleptics by the use of poorly water-soluble salts suchas the pamoates proved to be little successful (e.g. Florence et al.,1976, J. Pharm. Sci., 65(11), 1665-1668). Unexpectedly, the use of thepamoate salt of risperidone in dogs significantly prolonged the releaseof risperidone, yielding plasma levels of risperidone and its activemetabolite that were effective against apomorphine induced emesis duringseveral weeks.

Accordingly, the present invention is concerned with the pamoate acidaddition salts of risperidone. In particular, the invention is concernedwith the compound having the formula ##STR1## The period during whicheffective plasma levels are obtained depends on the physicalcharacteristics of the risperidone pamoate powder sample, such asparticle size and crystal form.

Risperidone, its preparation and the pharmacological activity thereofare described in EP-0,196,132. The pamoate salt of risperidone can beprepared by the treatment of risperidone with parnoic acid or a saltderivative thereof, e.g. the disodium pamoate, in a reaction-inertsolvent. In particular, risperidone pamoate can be prepared by adding asolution of risperidone in an appropriate solvent, e.g. ethanol, to asolution of pamoic acid in an appropriate solvent, e.g.N,N-dimethylformamide, and stirring the mixture until precipitation ofthe risperidone pamoate salt. The reaction product may be isolated fromthe medium and, if necessary, further purified according tomethodologies generally known in the art such as, for example,extraction, crystallization and chromatography. Micronized forms of thesubject compounds can be prepared by micronization techniques known inthe art, e.g. by milling in appropriate mills and sieving throughappropriate sieves.

In a particular aspect, the invention relates to the mixed pamoateaddition salts of risperidone, e.g. the monosodium pamoate salt ofrisperidone.

The subject compounds are potent antagonists of neurotransmitters and inparticular of dopamine. Antagonizing said neurotransmitter suppresses avariety of phenomena induced by the release, in particular the excessiverelease, of dopamine. Central dopamine receptor blockers are known tohave neuroleptic properties, for example, they counteract the positivesymptoms of schizophrenia, e.g. hallucinations, delusional thinking,severe excitement and unusual behaviour. Therapeutic indications forusing the present compound therefore are mainly in the CNS area,particularly as potent antipsychotic agents and especially as agentsuseful in treating chronic psychoses. The present compounds also showcentral serotonin antagonism. Central acting serotonin antagonistsappear to improve the negative symptoms of schizophrenia, e.g. anergy,apathy, social withdrawal and depressive mood, and also to reduce theincidence of extrapyramidal side-effects (EPS) during maintenancetherapy with classical neuroleptics, i.e. dopamine antagonists. Combineddopamine-serotonin antagonists are especially interesting as they offerrelief of both the positive and negative symptoms of schizophrenia withlow EPS liability.

The subject compounds show the advantage of being long acting dopamineantagonists by the sustained release of risperidone from the poorlywater-soluble pamoate salts. This can be evidenced, for example, bymeasuring the plasma levels after intramuscular or subcutaneousadministration to dogs and by the long acting antiemetic effect exertedby the present compounds on dogs challenged with the dopamine agonistapomorphine. Hence, the subject compounds allow administration atrelatively large intervals, e.g. at several weeks, the actual time ofadministration depending on the physical nature of the compound used andthe condition of the subject to be treated. Consequently, the presentcompounds allow for a more efficient therapy: the sustained releasefacilitates maintaining a stable plasma concentration at a non-toxic,effective level and the route of administration enhances compliance ofthe subject to be treated with the prescribed medication.

Unlike most of the currently available long-acting neuroleptics whichare usually formulated in an oil for intramuscular administration, thesubject compounds show the advantage that they can be formulated in bothlipophilic (e.g. an oil) and lipophobic solvents (e.g. aqueousenvironment) and may be administered in various ways, e.g.intramusculary or subcutaneously.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes. To prepare the pharmaceutical compositions ofthis invention, an effective amount of the subject compounds as theactive ingredient is combined in intimate admixture with apharmaceutically acceptable carder, which carder may take a wide varietyof forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administrationsubcutaneously or intramusculary. For the latter administration routes,the subject compounds preferably are suspended in an aqueous solvent,which may further comprise a wetting agent, such as the polyoxyethylenederivatives of sorbitan esters, e.g. polysorbate 80 (=Tween 80®) andpolysorbate 20 (=Tween 20®), lecithin, polyoxyethylene- andpolyoxypropylene ethers, sodium deoxycholate, and the like; a suspendingagent such as a cellulose derivate, e.g. methylcellulose, sodiumcarboxymethylcellulose and hydroxypropyl methylcellulose,polyvinylpyrrolidone, alginates, chitosan, rextrans, gelatin,polyethylene glycols, polyoxyethylene- and polyoxypropylene ethers andthe like; an acid, e.g. hydrochloric acid, and the like; a base, e.g.sodium hydroxide, and the like; a buffer comprising a mixture ofappropriate amounts of an acid such as phosphoric, succinic, tartaric,lactic, acetic, maleic or citric acid, and a base, in particular sodiumhydroxide or disodium hydrogen phosphate; a preservative, e.g. benzoicacid, benzyl alcohol, butylated hydroxyanisole, butylatedhydroxytoluene, chlorbutol, a gallam, a hydroxybenzoate, EDTA, phenol,chlorocresol, metacresol, benzothonium chloride, myristyl-γ-piccoliniumchloride, phenylmercuri acetate, thimerosal and the like; a tonicityadjusting agent, e.g. sodium chloride, dextrose, mannitol, sorbitol,lactose, sodium sulfate, and the like Alternatively, the subjectcompounds may be formulated in an oil. Appropriate oils for this purposeare fixed oils, for example, peanut oil, sesame oil, cottonseed oil,corn oil, safflower oil, castor oil, ethyloleate, soy bean oil,synthetic glycerol esters of long chain fatty or medium chain acids andmixtures of these and other oils.

Also thickening agents may be added to the composition, e.g. aluminummonostearate, ethylcellulose, triglycerides, hydrogenareal castor oil,and the like.

In view of the usefulness of the subject compounds in the treatment ofpsychotic diseases it is evident that the present invention provides amethod of treating warm-blooded animals, in particular humans, sufferingfrom psychotic diseases, said method comprising the administration of apharmaceutically effective amount of the subject compounds in admixturewith a pharmaceutical carder. In a further aspect, the present inventionrelates to the use of the subject compounds as a medicine, particularlyas an antipsychotic. In general it is contemplated that an effectiveamount would be from 0.05 mg/kg to 50 mg/kg body weight, more preferablyfrom 0.5 mg/kg to 10 mg/kg body weight.

The following examples are intended to illustrate and not to limit thescope of the present invention.

EXAMPLE 1

A solution of3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(0.048 mol) in ethanol (600 ml) was added to a solution of pamoic acid(0.048 mol) in N,N-dimethylformamide (400 ml). The mixture was stirredfor 3 hours. The resulting precipitate was filtered off by suction,washed with ethanol and dried, yielding 31 g (81%) of3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2a]pyrimidin-4-one4,4'-methylenebis[3-hydroxy-2-naphthalenecarboxylate] (1:1); mp. 269.2°C.

EXAMPLE 2

F1: aqueous suspension

    ______________________________________                                        risperidone monopamoate                                                                          25          mg                                             polysorbate 20     1           mg                                             benzyl alcohol     10          mg                                             purified water     q.s. 1      ml                                             ______________________________________                                    

The risperidone monopamoate, polysorbate 20, benzyl alcohol and purifiedwater were intimately mixed and homogenized, thus yielding an aqueoussuspension.

In a similar way there were prepared:

F2: aqueous suspension

    ______________________________________                                        risperidone monopamoate                                                                            50        mg                                             polysorbate 20       2         mg                                             benzyl alcohol       15        mg                                             sodium carboxymethylcellulose                                                                      20        mg                                             purified water       q.s. 1    ml                                             ______________________________________                                    

F3: suspension in oil

    ______________________________________                                        risperidone monopamoate                                                                          50          mg                                             sesame oil         q.s. 1      ml                                             ______________________________________                                    

EXAMPLE 3

The prolonged action of the risperidone monopamoate salt over therisperidone free base was established by the following procedure

The apomorphine test in dogs

The method used is described by P. A. J. Janssen and C. J. E. Niemegeersin Arzneim.-Forsch. (Drug Res.), 9, 765-767 (1959). A suspension of therisperidone free base in sesame oil and the risperidone monopamoatecompositions F1, F2 and F3 were administered to 3 beagle dogs at a dosebetween 2 and 2.5 mg/kg. The risperidone free base formula as well as F1and F3 were administered intramusculary, whereas F2 was administeredsubcutaneously. At several time intervals thereafter, the animals werechallenged with a standard dose of 0.31 mg/kg (subcutaneous) ofapomorphine, which is a potent dopamine agonist and induces emesis. Theantiemetic effect of the test compound was used as an indication of itsactivity.

The table hereinbelow summarizes the mean period of activity (days) thatwas obtained in the 3 test animals.

    ______________________________________                                                     Mean period of activity (days)                                   ______________________________________                                        Risperidone in sesame oil                                                                     3                                                             F1             22                                                             F2             18                                                             F3             12                                                             ______________________________________                                    

From the table it is clear that the administration of risperidonepamoate resulted in a significantly longer period of activity whencompared to the administration of the risperidone free base.

We claim:
 1. A compound which is a pamoate acid addition salt ofrisperidone.
 2. A compound according to claim 1 having the formula##STR2##
 3. A composition comprising a pharmaceutically acceptablecarrier and as active ingredient a pharmaceutically effective amount ofa compound as claimed in claim
 1. 4. A composition according to claim 3in an injectable dosage form.
 5. A composition according to claim 4which takes the form of an aqueous suspension.
 6. A compositionaccording to claim 5 further comprising benzyl alcohol, a sorbitan esterand water.
 7. A composition according to claim 6 further comprising acellulose derivative.